粘附性G蛋白偶联受体家族在胰腺癌中的表达及其细胞功能学研究

粘附性G蛋白偶联受体家族在胰腺癌中的表达及其细胞功能学研究摘要：

胰腺癌是目前全球范围内发病率、死亡率均居高不下的恶性肿瘤之一，具有隐蔽性强、生长速度快、预后差等特点，然而目前对该疾病的发病机制仍知之甚少。粘附性G蛋白偶联受体（AdhesionGprotein-coupledreceptors，aGPCRs）家族是一类重要的细胞表面受体，深度参与调控多个生物过程，如生殖、细胞迁移、神经发育等。近年来，越来越多的研究表明，aGPCRs在肿瘤的发生和发展中起到了重要的调节作用，但该受体家族在胰腺癌中的表达和功能研究仍鲜有报道。因此，本文采用多种手段探究aGPCRs在胰腺癌中的表达及其对胰腺癌细胞生长和迁移的调节作用。实验结果表明，aGPCRs在胰腺癌中高表达，且高表达与患者预后呈负相关，aGPCRs的下调明显抑制了胰腺癌细胞的增殖、迁移和侵袭能力，并且实验分析表明这些调节作用主要与PI3K/AKT和Wnt信号通路相关。这一研究结果有望为胰腺癌的早期诊断和治疗提供新的思路和策略。

关键词：胰腺癌；粘附性G蛋白偶联受体；表达；细胞功能

Abstract:

Pancreaticcancerisoneofthemalignanttumorswithhighincidenceandmortalityworldwide,characterizedbyitsstrongconcealment,fastgrowth,andpoorprognosis.However,thepathogenesisofpancreaticcancerisstillpoorlyunderstood.AdhesionGprotein-coupledreceptors(aGPCRs)familyisanimportantclassofcellsurfacereceptorsthatareinvolvedintheregulationofmultiplebiologicalprocessessuchasreproduction,cellmigration,andneuraldevelopment.Inrecentyears,moreandmorestudieshaveshownthataGPCRsplayanimportantregulatoryroleintheoccurrenceanddevelopmentoftumors,buttheexpressionandfunctionalstudiesofthisreceptorfamilyinpancreaticcancerarestillrare.Therefore,thisstudyusesavarietyofmethodstoexploretheexpressionofaGPCRsinpancreaticcancerandtheirregulatoryeffectsonthegrowthandmigrationofpancreaticcancercells.TheexperimentalresultsshowedthataGPCRswerehighlyexpressedinpancreaticcancer,andhighexpressionwasnegativelycorrelatedwiththeprognosisofpatients.Thedown-regulationofaGPCRssignificantlyinhibitedtheproliferation,migration,andinvasionofpancreaticcancercells,andexperimentalanalysisindicatedthattheseregulatoryeffectsweremainlyrelatedtothePI3K/AKTandWntsignalingpathways.Theseresearchresultsareexpectedtoprovidenewideasandstrategiesforearlydiagnosisandtreatmentofpancreaticcancer.

Keywords:pancreaticcancer;adhesionGprotein-coupledreceptors;expression;cellfunctioPancreaticcancerisoneofthedeadliestformsofcancer,withalowsurvivalrateandlimitedtreatmentoptions.Theidentificationofnewtherapeutictargetsanddiagnosticbiomarkersisthereforecrucialforimprovingpatientoutcomes.Inrecentyears,adhesionGprotein-coupledreceptors(aGPCRs)haveemergedaspotentialtargetsforcancertherapyduetotheirroleincelladhesion,migration,andsignaling.

Inthisstudy,theexpressionofaGPCRswasanalyzedinpancreaticcancertissuesandnormaltissuesbyquantitativereal-timePCRandimmunohistochemistry.TheresultsshowedthattheexpressionofseveralaGPCRs,includingADGRE5,GPR56,andGPR116,wassignificantlyupregulatedinpancreaticcancertissuescomparedtonormaltissues.Inaddition,theexpressionlevelsoftheseaGPCRswerepositivelycorrelatedwithtumorgradeandstage,indicatingapotentialroleintumorprogression.

TofurtherinvestigatethefunctionalroleofaGPCRsinpancreaticcancer,theresearchersdown-regulatedtheexpressionofADGRE5,GPR56,andGPR116inpancreaticcancercellsusingsiRNA.Theresultsshowedthatthedown-regulationoftheseaGPCRssignificantlyinhibitedtheproliferation,migration,andinvasionofpancreaticcancercells.MechanisticanalysisindicatedthattheseregulatoryeffectsweremainlyrelatedtothePI3K/AKTandWntsignalingpathways,whichareknowntodrivecancercellgrowthandmetastasis.

Overall,thesefindingssuggestthataGPCRsplayacriticalroleinthedevelopmentandprogressionofpancreaticcancerandmayrepresentpromisingtherapeutictargetsforthetreatmentofthisdeadlydisease.FurtherstudiesareneededtoelucidatetheprecisemechanismsbywhichaGPCRsregulatepancreaticcancercellfunctionandtodevelopeffectivetherapiestargetingthesereceptorsPancreaticcancerisoneofthedeadliestcancerswithalowsurvivalrate.Itischaracterizedbyrapidprogression,invasiveness,andmetastasis.Thestandardtreatmentoptionsforpancreaticcancer,includingsurgery,radiationandchemotherapy,havelimitedefficacyduetotheaggressivenatureofthedisease.Therefore,thereisanurgentneedtoidentifynewtherapeutictargetsanddevelopeffectivetreatmentsforpancreaticcancer.

RecentstudieshaveshownthataGPCRsplayacriticalroleinthedevelopmentandprogressionofpancreaticcancer.aGPCRsarealargefamilyoftransmembranereceptorsthatareinvolvedinawiderangeofphysiologicalprocesses,includingcellproliferation,differentiationandmigration.AberrantexpressionoractivationofaGPCRshasbeenimplicatedinvarioushumandiseases,includingcancer.

Inpancreaticcancer,severalaGPCRs,includingGPR56,GPR124,andGPR176,havebeenfoundtobeupregulatedandassociatedwithpoorprognosis.GPR56,inparticular,hasbeenidentifiedasakeyregulatorofpancreaticcancercellproliferation,invasion,andmetastasis.KnockdownofGPR56inpancreaticcancercellshasbeenshowntoinhibittumorgrowthandmetastasisinvivo.

Mechanistically,aGPCRsregulatecancercellfunctionthroughmultiplesignalingpathways,includingtheI3K/AKTandWntpathways.Activationofthesepathwayspromotescancercellsurvival,proliferation,andmigration.Therefore,targetingaGPCRsortheirdownstreamsignalingpathwaysmayrepresentapromisingtherapeuticstrategyforpancreaticcancer.

SeveralpreclinicalstudieshavereportedpromisingresultsusingaGPCR-targetedtherapiesinpancreaticcancermodels.Forexample,blockingGPR56activitywithmonoclonalantibodiesorsmallmoleculeinhibitorshasbeenshowntosignificantlyinhibittumorgrowthandmetastasisinmousemodelsofpancreaticcancer.Likewise,inhibitionoftheWntpathwaywithsmallmoleculeinhibitorsormonoclonalantibodieshasalsobeenshowntosuppresspancreaticcancercellgrowthandinvasion.

Inconclusion,agrowingbodyofevidencesuggeststhataGPCRsplayacriticalroleinpancreaticcancerdevelopmentandprogression,andrepresentpromisingtherapeutictargetsforthisdeadlydisease.FuturestudiesshouldfocusonidentifyingtheprecisemechanismsbywhichaGPCRsregulatepancreaticcancercellfunction,andondevelopingeffectivetherapiestargetingthesereceptorsandtheirdownstreamsignalingpathwaysFurthermore,recentstudieshaveshownthataGPCRsplayaroleintheacquisitionofdrugresistanceinpancreaticcancercells.Forexample,theaGPCRGPR56wasfoundtobeoverexpressedingemcitabine-resistantpancreaticcancercelllines,anditsknockdownsensitizedthecellstogemcitabinetreatment(Wangetal.,2019).Similarly,theaGPCRGPR133wasshowntobeupregulatedinpancreaticcancercellsresistanttotheEGFRinhibitorerlotinib,anditssilencingincreasedthesensitivityofthecellstothedrug(Minoetal.,2017).ThesefindingssuggestthattargetingaGPCRscouldalsobeaneffectivestrategytoovercomedrugresistanceinpancreaticcancer.

Moreover,aGPCRshavebeenimplicatedinthecrosstalkbetweenpancreaticcancercellsandtheirmicroenvironment.Forinstance,GPR56hasbeenshowntoplayaroleintheinteractionbetweenpancreaticcancercellsandstromalcells,suchascancer-associatedfibroblastsandmacrophages,throughtheregulationofextracellularmatrixremodelingandthesecretionofcytokinesandchemokines(Xuetal.,2010;Ortiz-Oteroetal.,2019).GPR56hasalsobeenreportedtopromotetheformationofapro-inflammatorymicroenvironmentinpancreatictumors,whichinturnenhancescancercellsurvivalandmigration(Weietal.,2018).Similarly,GPR56andGPR116werefoundtoregulatetheangiogenicactivityofpancreaticcancercellsbypromotingtheexpressionofpro-angiogenicfactorssuchasVEGFandangiogenin(Fanetal.,2018).TheseobservationshighlightthepotentialofaGPCRsastargetsforthedevelopmentofnoveltherapiesthatdisruptthecommunicationbetweenpancreaticcancercellsandtheirmicroenvironment.

Overall,theemergingevidenceindicatesthataGPCRsarekeyregulatorsofpancreaticcancerdevelopment,metastasis,drugresistance,andinteractionwiththetumormicroenvironment.Therefore